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WO2020207355A1 - Composition pharmaceutique contenant de l'amlodipine, de la chlortalidone et de l'amiloride - Google Patents

Composition pharmaceutique contenant de l'amlodipine, de la chlortalidone et de l'amiloride Download PDF

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Publication number
WO2020207355A1
WO2020207355A1 PCT/CN2020/083332 CN2020083332W WO2020207355A1 WO 2020207355 A1 WO2020207355 A1 WO 2020207355A1 CN 2020083332 W CN2020083332 W CN 2020083332W WO 2020207355 A1 WO2020207355 A1 WO 2020207355A1
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Prior art keywords
pharmaceutical composition
amlodipine
chlorthalidone
amiloride
group
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Ceased
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PCT/CN2020/083332
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English (en)
Chinese (zh)
Inventor
陈光亮
于多
白洁
田敏卿
陈平
徐希平
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SHENZHEN AUSA PHARMACEUTICAL Co Ltd
SHENZHEN AUSA PHARMED CO Ltd
Original Assignee
SHENZHEN AUSA PHARMACEUTICAL Co Ltd
SHENZHEN AUSA PHARMED CO Ltd
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Priority to CN202080003993.1A priority Critical patent/CN115243774B/zh
Publication of WO2020207355A1 publication Critical patent/WO2020207355A1/fr
Priority to US17/489,575 priority patent/US12336978B2/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/4035—Isoindoles, e.g. phthalimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the invention provides a pharmaceutical composition for treating refractory hypertension, which is composed of amlodipine, chlorthalidone and amiloride. It belongs to the field of pharmacy.
  • Refractory hypertension (resistant hypertension, RH) accounts for about 15-20% of all hypertension patients.
  • RH resistant hypertension
  • 3 kinds of antihypertensive drugs including diuretics
  • blood pressure still does not reach the target, or taking ⁇ 4 kinds of antihypertensive drugs Effective control is called RH [Chinese Expert Consensus on Diagnosis and Treatment of Refractory Hypertension, Chinese Journal of Hypertension, 2013, 21(4), 321-326].
  • the etiology and pathophysiological mechanisms of RH are multifaceted. There are basic causes, as well as central and local neurohumoral mechanisms.
  • rennin-angiotensin-aldosterone system rennin-angiotensin-aldosterone system
  • the oxidative stress process also promotes the occurrence and progression of arteriosclerosis and atherosclerosis, and aggravates the abnormalities of blood vessel structure and function, making it difficult to control the increased blood pressure.
  • RH not only has the "refractory" characteristic of lowering blood pressure, it is more likely to be combined with target organ damage and increase the prevalence of heart, cerebrovascular and kidney diseases.
  • RASI angio-tensin converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB)]
  • ACEI angio-tensin converting enzyme inhibitor
  • ARB angiotensin receptor blocker
  • clonidine, proserpine, and central nervous system inhibitory drugs can be used as the fifth antihypertensive drug of the combined program.
  • RH central nervous system inhibitory drugs
  • the treatment of RH drugs is still in the development stage.
  • the drugs in the patents for the treatment of RH that have been published in China all contain traditional Chinese medicine ingredients.
  • Chinese patent application 201710585463.2 combines Ganoderma lucidum polysaccharides with multiple antihypertensive drugs in conventional multi-therapy.
  • Chinese patent 201110086573.7 discloses a Chinese patent medicine for the treatment of refractory hypertension, which is composed of sea buckthorn, thyme, periwinkle, ganoderma, black fungus, amla root, rhodiola, and Rauvolu , Pueraria lobata, Hawthorn, Cassia seed.
  • refractory hypertension which is composed of sea buckthorn, thyme, periwinkle, ganoderma, black fungus, amla root, rhodiola, and Rauvolu , Pueraria lobata, Hawthorn, Cassia seed.
  • the mechanism of action of traditional Chinese medicine is complex, usually slow and effective, and the treatment period is longer.
  • the blood pressure of RH patients remains high for a long time, it will cause greater harm, which is inconsistent with the characteristics of traditional Chinese medicine treatment.
  • Amlodipine belongs to the long-acting dihydropyridine calcium channel blocker. It blocks the extracellular calcium ion of vascular smooth muscle from entering the cell through the calcium ion channel of the cell membrane, directly relaxes the vascular smooth muscle, expands peripheral blood vessels, and reduces peripheral resistance. It is clinically used Treat high blood pressure and angina pectoris. Compared with similar drugs, amlodipine lasts for a long time, has fewer side effects and is mild, and is the first-line drug for the clinical treatment of hypertension.
  • Chlorthalidone inhibits the Na + -Cl - symporter at the beginning of the distal convoluted tubules of the kidney, reduces the reabsorption of Na + , Cl - and water, and excretes excessive sodium and water in the body to reduce the extracellular fluid volume Reduce swelling.
  • the causes of edema include congestive heart failure, acute emphysema, liver disease, ascites, nephrotic syndrome, acute and chronic nephritis, etc.
  • Chlorthalidone is an auxiliary drug for the treatment of these diseases. In terms of lowering blood pressure, chlorthalidone is mainly used to treat mild and moderate hypertension, elderly hypertension complicated by heart failure and other diseases.
  • Amiloride is a potassium-sparing diuretic that acts on the distal renal tubules and collecting ducts, blocks sodium channels, inhibits the exchange of Na + -H + and Na + -K + , promotes the excretion of sodium and chlorine and reduces K + , H + secretion, its own urinary sodium excretion and anti-hypertensive activity is weak, suitable for chronic congestive heart failure, liver cirrhosis with ascites, and hypokalemia caused by primary aldosteronism.
  • the existing antihypertensive compound drugs are mainly for hypertension, not RH.
  • the compound products composed of three antihypertensive drugs on the domestic and foreign markets include amlodipine, valsartan, hydrochlorothiazide, amlodipine, telmisartan, hydrochlorothiazide, etc., and their indications are essential hypertension and are not used for hypertension.
  • Initial treatment There are also many compound or combination drugs in the research stage.
  • Chinese Patent 201010116867.5 discloses a compound pharmaceutical composition containing levalamlodipine for the treatment of hypertension, which includes levalamlodipine or its pharmaceutically acceptable Salt, and chlorthalidone.
  • Renin and aldosterone should be regarded as biomarkers, and their plasma concentrations in RH patients should be measured. According to the difference between the two, the pathophysiological analysis of RH can be carried out. Type, so that clinical medication is more targeted. According to plasma renin and aldosterone levels, RH patients can be divided into low renin/high aldosterone, low renin/low aldosterone, and high renin/high aldosterone.
  • the purpose of the present invention is to provide a pharmaceutical composition with significant curative effect for RH, especially low renin/low aldosterone RH patients.
  • a pharmaceutical composition for RH consisting of
  • amlodipine may exist in the form of salts, esters, active metabolites, or pharmaceutical precursors.
  • the amlodipine provided by the present invention is used as a pharmaceutical ingredient, and its salt, ester, active metabolite or medicinal precursor and other forms of amlodipine are also within the protection scope of this application.
  • the pharmaceutical dosage of amlodipine is selected from 2.5-10 mg, preferably 5-10 mg.
  • the medicinal dosage of amlodipine in the form of salts, esters, active metabolites or medicinal precursors can be converted accordingly.
  • chlorthalidone may exist in the form of salts, esters, active metabolites, or pharmaceutical precursors.
  • the chlorthalidone provided by the present invention is used as a pharmaceutical ingredient, and the existing forms of chlorthalidone salts, esters, active metabolites or pharmaceutical precursors are also within the protection scope of the application.
  • the pharmaceutical dosage of chlorthalidone is selected from 12.5-100 mg, preferably 12.5-50 mg.
  • the medicinal doses of chlorthalidone in the form of salts, esters, active metabolites or medicinal precursors can be converted.
  • amiloride in the pharmaceutical composition provided by the present invention, can exist in the form of salts, esters, active metabolites, or pharmaceutical precursors.
  • the amiloride provided by the present invention is used as a pharmaceutical ingredient, and its salts, esters, active metabolites or pharmaceutical precursors are also within the scope of protection of the application.
  • the pharmaceutical dosage of amiloride is selected from 2.5-20 mg, preferably 5-10 mg.
  • the medicinal dosages of amiloride in the form of salts, esters, active metabolites or medicinal precursors can be converted into each other.
  • the medicinal dosage of the active ingredient of the composition refers to the dosage range of the medicinal ingredient in the composition to make the composition exert medicinal effect after being combined with other medicinal ingredients.
  • the preferred dose is the preferred medicinal dose of the active ingredient of the composition, and the medicinal effect of the preferred dose is better than that of the medicinal dose.
  • the pharmaceutical dosage of the active ingredient of the composition includes the optimal dosage or optimal dosage range that maximizes the efficacy of the composition, and the optimal dosage or optimal dosage range will benefit the patient more.
  • the composition of the pharmaceutical composition provided by the present invention is 5 mg amlodipine, 12.5 mg chlorthalidone and 5 mg amiloride.
  • composition of the pharmaceutical composition provided by the present invention is 5 mg amlodipine, 12.5 mg chlorthalidone and 10 mg amiloride.
  • composition of the pharmaceutical composition provided by the present invention is 5 mg amlodipine, 25 mg chlorthalidone and 5 mg amiloride.
  • composition of the pharmaceutical composition provided by the present invention is 5 mg amlodipine, 25 mg chlorthalidone and 10 mg amiloride.
  • composition of the pharmaceutical composition provided by the present invention is 5 mg amlodipine, 50 mg chlorthalidone and 10 mg amiloride.
  • composition of the pharmaceutical composition provided by the present invention is 10 mg amlodipine, 12.5 mg chlorthalidone and 5 mg amiloride.
  • composition of the pharmaceutical composition provided by the present invention is 10 mg amlodipine, 12.5 mg chlorthalidone and 10 mg amiloride.
  • composition of the pharmaceutical composition provided by the present invention is 10 mg amlodipine, 25 mg chlorthalidone and 5 mg amiloride.
  • composition of the pharmaceutical composition provided by the present invention is 10 mg amlodipine, 25 mg chlorthalidone and 10 mg amiloride.
  • the pharmaceutical composition also contains a pharmaceutically acceptable carrier, which can be made into ordinary oral preparations, including ordinary tablets, ordinary capsules, granules, etc., when the pharmaceutical composition is made into tablets, the pharmaceutically acceptable carriers include
  • a pharmaceutically acceptable carrier which can be made into ordinary oral preparations, including ordinary tablets, ordinary capsules, granules, etc., when the pharmaceutical composition is made into tablets
  • the pharmaceutically acceptable carriers include
  • the compound is formulated into excipients and adjuvants for medicinal preparations, such as a combination of one or more substances such as microcrystalline cellulose, inorganic salts, lactose, sodium chloride, citric acid and sodium sulfite, which belongs to common knowledge in the art.
  • the pharmaceutical composition provided by the invention provides an effective antihypertensive drug for RH patients, especially low renin/low aldosterone RH patients.
  • the medicinal active ingredients of the pharmaceutical composition provided by the present invention are amlodipine, chlorthalidone and amiloride, the composition is rapid in treating RH and has significant curative effect, and is especially suitable for patients with low renin/low aldosterone RH .
  • Amlodipine, chlorthalidone and amiloride are all commonly used antihypertensive drugs. As described in the background art, the above drugs can be used alone or in combination with other antihypertensive drugs, and can also be used for hypertension However, there is no effective treatment for RH.
  • the combination of amlodipine, chlorthalidone and amiloride has a significant effect in the treatment of RH, which is not a single agent or a combination of two.
  • the antihypertensive effect of the pharmaceutical composition provided by the present invention lasts for a long time, the blood pressure fluctuations are small throughout the day after the patient takes it, and once a day is taken, the blood pressure can be stabilized for 24 hours.
  • the pharmaceutical composition provided by the present invention can also enhance the protective effect on the target organs of patients with RH, while reducing the risk of cardiovascular and cerebrovascular events.
  • Target organ damage caused by RH includes left ventricular hypertrophy, benign arteriole nephrosclerosis, malignant arteriole nephrosclerosis, renal failure, retinal arteriosclerosis, or hypertensive fundus disease.
  • cerebrovascular events including cerebral infarction and cerebral hemorrhage will occur, that is, stroke.
  • the pharmaceutical composition provided by the present invention not only effectively lowers blood pressure but also lowers blood pressure steadily within 24 hours.
  • RH blood pressure fluctuations throughout the day are small, and the damage to important organs caused by the increase in blood pressure and rapid blood pressure fluctuations is reduced.
  • RH easily induces vascular remodeling and endothelial dysfunction, as well as sympathetic nerve and renin-angiotensin system over-activation, metabolic abnormality and inflammation.
  • the three medicinal components of the pharmaceutical composition provided by the present invention exert their respective mechanisms of action. Significantly synergistically improve these non-hemodynamic changes caused by elevated blood pressure, thereby effectively protecting the target organs of RH patients.
  • the content of the drug provided by the present invention is not a limitation of the present invention, but a preference for the present invention. Under normal circumstances, within this content range, the drug can produce effective therapeutic effects on diseased individuals.
  • a diseased individual refers to an independent living body suffering from a disease, and in the present invention, a living body especially refers to a human being.
  • human medicinal content or medicinal content range can be converted with mammals, such as rats, mice, etc., to obtain a medicinal content or content range suitable for corresponding animals.
  • Example 1-Example 11 Preparation of amlodipine, chlorthalidone and amiloride tablets (1000 tablets)
  • amlodipine, chlorthalidone and amiloride add sodium starch glycolate, sodium lauryl sulfate and mix, then add microcrystalline cellulose and pregelatinized starch to mix well, use appropriate amount of 10% polyvinyl
  • the ketone-ethanol solution is made into a soft material, granulated, dried, and granulated.
  • the granules with a water content of about 3% and an appropriate amount of magnesium stearate are mixed uniformly, and then compressed into 1000 tablets.
  • Example 12 Preparation of amlodipine, chlorthalidone and amiloride capsules (1000 capsules)
  • the lactose, microcrystalline cellulose, and sodium starch glycolate and dry them at about 100°C for about 2 hours. Pass the sodium starch glycolate through a 100 mesh sieve, and the lactose and microcrystalline cellulose through an 80 mesh sieve; After passing through a 100-mesh sieve, it is mixed with the above-mentioned auxiliary material mixture uniformly, granulated, then mixed with an appropriate amount of behenic acid glyceride, and filled with No. 3 capsules. Get it when made into 1000 tablets.
  • Example 13 Preparation of amlodipine, chlorthalidone and amiloride capsules (1000 capsules)
  • Example 14 The effect of amlodipine/chlorthalidone/amiloride compound preparation on lowering blood pressure and target organ protection in DOCA salt hypertensive rats
  • Animal model preparation 94 SD rats, weighing 200-220g, males, fed with ordinary dietary feed, 7 days after quarantine, check the basal blood pressure, randomly select 10 rats as the sham operation group, and continue feeding with ordinary feed until the end of the experiment .
  • the remaining 84 rats were used as the model group, and DOCA silicone tubes (100 mg/mouse) were implanted subcutaneously. Rats in the model group were anesthetized by intraperitoneal injection of 0.8% pentobarbital sodium.
  • the left kidney was removed first, the dorsal position was fixed, the left and right sides of the abdomen were clipped, routinely disinfected, the left abdominal cavity was cut, about 3 cm long, and the left For the kidney, first ligate the renal arteries and veins.
  • blood pressure measurement was performed 4 weeks after the model was modeled. If the blood pressure was stable above 140mmHg, the model was successfully modeled. 70 rats that were successfully modeled were stratified and randomly divided into model group and drug group according to their blood pressure. There are 10 animals in each group, the administration volume is 1ml/100g body weight, once a day for 13 weeks.
  • the control drug was amlodipine, valsartan, hydrochlorothiazide tablets, the dual drug was a combination of raw materials, and the test drug was the compound preparation prepared in Examples 5 and 11, and the body surface area was converted into the required dose for rats.
  • Detection indicators (1) After modeling, the serum renin and aldosterone levels of rats before administration were detected after grouping; (2) Blood pressure was measured before administration and 4 weeks after administration, 8 weeks after administration, and 13 weeks after administration (3) Renal function indicators: urine protein, microalbumin, creatinine clearance, urea nitrogen; (4) Heart function: left ventricular index, heart index, brain natriuretic peptide level.
  • the creatinine clearance rate of the model decreased and the urea nitrogen level increased significantly, which was significantly different from the sham operation group.
  • the creatinine clearance rate of the amlodipine, chlorthalidone, and amiloride tablets administration group increased, and the urea nitrogen decreased, and the triple drug combination was effective
  • the triple drug can further improve renal function, indicating that the compound preparation group has a significant protective effect on the kidney.
  • Brain natriuretic peptide (BNP) gene is an acute phase response gene of the heart, which can be used when myocardial ischemia and ventricular wall stress increase. Stimulate the synthesis and release of brain natriuretic peptide. After 13 weeks of administration, the animals were sacrificed and blood was collected to detect the plasma brain natriuretic peptide level, the heart was weighed, and the left ventricle was separated and weighed. The left ventricular index ((left ventricle/heart weight*1000)/body weight of each group was calculated ).
  • the left ventricular index of the model group increased significantly, indicating that there is left ventricular hypertrophy.
  • Amlodipine, valsartan, hydrochlorothiazide tablets have a certain improvement effect, but the effect is not as good as amlodipine, chlorthalidone, amiloride tablets Administration group (P ⁇ 0.05).
  • the BNP of the model group was significantly increased, suggesting that there was an acute cardiac reaction.
  • the BNP of the amlodipine, chlorthalidone, and amiloride tablets administration group was significantly lower (P ⁇ 0.01). Compared with the dual drug combination, the cardioprotective effect was more obvious . See Table 4.
  • Example 15 Synergistic effect of amlodipine/chlorthalidone/amiloride on lowering blood pressure in DOCA salt hypertensive rats
  • the model preparation method and dosing conversion are the same as in Example 14.
  • the animal groups are shown in Table 5. Each group of 10 animals was administered by gavage, once a day, for 4 consecutive weeks. The systolic blood pressure of the rats was measured 2 to 4 hours after the last administration.
  • the Jinzheng average Q value method is also called the probability addition method.
  • the Q value is less than 0.85
  • the combination of the two drugs is considered to be antagonistic
  • 0.85 is less than Q value is less than 1.15
  • Q value is greater than 1.15, it is considered to be synergistic.
  • the Q values of the Amlodipine/Chlorthalidone/Amiloride combination group on the systolic blood pressure of DOCA salt hypertensive rats were 1.257, 1.203, 1.295, all> 1.15
  • the pharmaceutical composition of the present invention has a synergistic effect with each other, and the compatibility of the three drugs is reasonable, which can enhance the antihypertensive effect of the drugs on DOCA salt hypertensive rats.
  • the amlodipine/hydrochlorothiazide/amiloride combination group has Q values of 1.022, 0.920, 0.986, 0.85 ⁇ Q value ⁇ for DOCA salt hypertensive rats. 1.15, indicating that the amlodipine/hydrochlorothiazide/amiloride pharmaceutical composition is additive to each other.
  • the Q values of the amlodipine/hydrochlorothiazide/spironolactone combination group on the systolic blood pressure of DOCA salt hypertensive rats were 0.956, 0.890, 0.901, 0.85 ⁇ Q value ⁇ 1.15, indicating that the combination of amlodipine/hydrochlorothiazide/spironolactone is mutually exclusive
  • the time is additive.
  • the Q values of the amlodipine/valsartan/hydrochlorothiazide combination group on the systolic blood pressure of DOCA salt hypertensive rats were 0.939, 1.010, 0.975, 0.85 ⁇ Q value ⁇ 1.15, indicating that amlodipine/valsartan/hydrochlorothiazide
  • the compositions are additive to each other.
  • the Q value of the amlodipine/chlorthalidone/spironolactone combination group on the systolic blood pressure of DOCA salt hypertensive rats were 0.977, 0.972, 0.85 ⁇ Q value ⁇ 1.15, respectively.
  • the amlodipine/chlorothalidone/spironolactone compositions are additive to each other.
  • the Q values of the amlodipine/valsartan/chlorthalidone combination group on the systolic blood pressure of DOCA salt hypertensive rats were 0.998, 1.022, 0.85 ⁇ Q value ⁇ 1.15, indicating that amlodipine/valsartan/chloride
  • the thioketone compositions are additive to each other.
  • Example 16 Clinical trial of amlodipine+chlorthalidone+amiloride on the antihypertensive efficacy and safety of RH patients
  • Selection criteria Subjects who meet all of the following criteria and no one of the exclusion criteria can be selected.
  • the subjects were randomly divided into groups and controlled in parallel.
  • the blood pressure of the patients was measured at the 4th weekend and 8th weekend respectively.
  • Patients with both systolic and systolic blood pressure ( ⁇ 140/90mmHg) were regarded as the blood pressure standard, and the standard rate was calculated.
  • Safety indicators include: blood and urine routine, electrocardiogram, liver and kidney function, and adverse events.
  • Group A Continue the original treatment plan
  • Group B Stop the original drug and switch to amlodipine/valsartan/hydrochlorothiazide tablets (10/160/25mg);
  • Group C Stop the original drug and switch to amlodipine 5-10 mg + chlorthalidone 12.5-50 mg + amiloride 5-10 mg
  • Common adverse events include: upper respiratory tract symptoms, pain, abnormal liver function, gastrointestinal symptoms, abnormal lipid metabolism, dizziness, skin itching, urinary system symptoms, cardiovascular symptoms, oral symptoms, abnormal glucose metabolism And facial flushing.
  • the total incidence of adverse events in group A was 22.0%, group B was 19.8%, group C was 15.6%, and group C had the lowest incidence of adverse events.
  • Example 17 Clinical trial of amlodipine + chlorthalidone + amiloride on the antihypertensive efficacy and safety of patients with low renin/low aldosterone RH
  • Selection criteria Subjects who meet all of the following criteria and no one of the exclusion criteria can be selected.
  • Group A Continue the original treatment plan
  • Group B Stop the original drug and switch to amlodipine/valsartan/hydrochlorothiazide tablets (10/160/25mg);
  • Group C Stop the original drug and switch to amlodipine 5-10 mg + chlorthalidone 12.5-50 mg + amiloride 5-10 mg
  • Common adverse events include: upper respiratory tract symptoms, abnormal liver function, gastrointestinal symptoms, abnormal lipid metabolism, dizziness, skin itching, urinary system symptoms, cardiovascular symptoms, abnormal glucose metabolism and facial flushing.
  • the total incidence of adverse events in group A was 25.6%, group B was 28.9%, group C was 18.9%, and group C had the lowest incidence of adverse events.

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Abstract

L'invention concerne une composition pharmaceutique pour le traitement de l'hypertension réfractaire. La composition pharmaceutique comprend de l'amlodipine, de la chlortalidone et de l'amiloride. La composition pharmaceutique selon l'invention fournit un médicament antihypertenseur efficace chez des patients atteints d'hypertension réfractaire, en particulier des patients atteints d'hypertension réfractaire avec un faible taux de rénine et d'aldostérone, et elle peut également améliorer l'effet de protection sur les organes cibles des patients atteints d'hypertension réfractaire et réduire le risque d'accidents vasculaires cérébraux.
PCT/CN2020/083332 2019-04-08 2020-04-03 Composition pharmaceutique contenant de l'amlodipine, de la chlortalidone et de l'amiloride Ceased WO2020207355A1 (fr)

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US17/489,575 US12336978B2 (en) 2019-04-08 2021-09-29 Pharmaceutical composition containing amlodipine, chlorthalidone, and amiloride and application thereof

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CN201910274749.8A CN111789843A (zh) 2019-04-08 2019-04-08 含氨氯地平、氯噻酮和阿米洛利的药物组合物

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US20220079920A1 (en) 2022-03-17
CN115243774B (zh) 2024-05-24
CN115243774A (zh) 2022-10-25
CN111789843A (zh) 2020-10-20

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